The insertion of a foreign inert substance into the body of a patient or subject results in a series of biochemical and cellular responses by the body which is termed the foreign body reaction. The clinical consequences of foreign body reaction include, for example, deposition of cells and collagenous matrix around the device; pain and swelling at the site of the biomaterial; scarring at the site of the biomaterials, limited function of the biomaterial and/or medical device. Currently, there are no effective therapeutic strategies which can limit foreign body reaction, although limited improvement (and numerous side effectis) has been seen with the administration of steroids.
Currently there are 8.7 million breast implantations each year with a complication rate, due to foreign body reaction, of approximately 5.3%. There are approximately 200,000 breast reconstruction surgeries a year with a complication rate of approximately 25%. There are approximately 175,000 coronary stents introduced into coronary vessels of patients every year, with a re-stenosis rate of approximately 15%. Neointimal tissue builds up inside the stent triggered by the inflammatory response (a type of foreign body reaction). Various long-term implantable sensors, which produce foreign body reaction resulting in device failure of approximately 100% and other devices are in clinical trials. Limitations on their use relates to the frequent occurrence of foreign body reaction (FBR) with the introduction of these devices into a patient.
Thus, there is a very large unmet need in a very large clinical area which is addressed by the present invention. The present inventors have demonstrated a role for the cellular machinery involved in sterile inflammation in a range of disease models and biological processes. These include sterile liver injury by acetaminophen (APAP), pancreatitis and the foreign body reaction to biomaterials. Important components of this machinery are membrane receptors which can detect cellular perturbation and cellular death. The present inventors have identified that TLR7 and TLR9 serve an important role in vivo by detecting cellular death. TLR7 and TLR9 serve this role by undergoing activation in response to endogenous cellular materials including nucleic acids. The inventors have shown that TLR7 and TLR9 results in initiation of a sterile inflammatory response to a wide range of clinically important conditions, including drug induced liver injury (for example, APAP among numerous others), non-alcoholic steatohepatitis, alcoholic steatohepatitis, and even hepatitis caused by viral infections, including hepatitis B and C. TLR7 and TLR9 also play an important role in a wide range of other types of inflammatory diseases, including pancreatitis and the inflammation caused by foreign body reaction to biomaterials as described above.